柚皮素自微乳不对称膜渗透泵胶囊的制备及体外评价

制备柚皮素自微乳不对称膜渗透泵胶囊并考察其体外释药行为。实验利用球晶技术进行自微乳的固化研究,以醋酸纤维素浓度、栓模浸入聚合物溶液中时间、栓模浸入淬火液中时间为自变量,采用星点设计-效应面优化法,以囊壳厚度和24h药物累积释放度为因变量,确定不对称膜渗透泵胶囊壳的最佳制备工艺。其最佳制备工艺为:醋酸纤维素浓度9.44%,栓模浸入聚合物溶液中时间3.77min,栓模浸入淬火液中时间15.86min,按最佳工艺得到的药物累积释放度为96.27%,囊壳厚度为0.275mm。体外释药行为符合零级释药方程(R=0.9997)。柚皮素自微乳不对称膜渗透泵胶囊可有效控制药物缓慢释放,解决难溶性药物制成渗透泵制剂释药不完全的问题。     

经皮给药载体载MD-CPT透明质酸纳米乳的细胞吞噬与体内药代动力学研究

本文在研究制备了包载10,11-亚甲二氧基喜树碱(MD-CPT)的透明质酸纳米乳(HANs)经皮给药系统的基础上,进一步研究了载MD-CPT透明质酸纳米乳的细胞吞噬,并进行了体内药代动力学分析.通过优化制备条件,得到了皮肤渗透性良好的缓释剂型.从CLSM观察到药物被细胞摄入并传递入细胞核,同时,载药纳米乳的细胞吞噬效率呈时间依赖性,不同细胞株HSF、HUVES、MCF-7、KF的细胞吞噬率略有不同.用Rhodanmine B标记HANs,通过荧光显微镜观察到载药纳米乳透过角质层到达真皮层的拟动态过程.利用HPLC检测MD-CPT血药浓度,测得经皮给药半衰期T1/2是静脉注射的3.6倍,肌肉注射的1.6倍,体内药物滞留时间显著增加;血药浓度峰谷值差异小,曲线平缓,说明经皮给药能保证血药浓度呈现可控的持续性.最终通过活体成像系统和组织切片荧光显微镜,直观地反映出经皮给药后药物在大鼠体内的分布情况和各组织器官药物含量,确定载药纳米乳主要采取胞间渗透的扩散方式,在局部给药的区域滞留时间较长,有利于对浅表性的病灶区持续给药,延长药效,而剩余的MD-CPT和解离的HANs都进入了血液循环,最终通过新陈代谢被排出体外.为无创型HANs经皮给药系统应用于浅表性肿瘤治疗提供了理论基础.     

不同类型口服缓控释制剂对体外释药的影响

目的:综述近年口服缓控释制剂剂型结构对体外释药的影响,为缓释制剂研究提供参考。方法:查阅近年国内外相关文献,对常见的骨架型、膜控型、渗透泵型、胃内滞留型、定时释药等口服缓控释制剂的剂型结构及其在人体外释放药物的作用范围和作用程度加以概述。结果:通过实验研究发现针对相同的药物可以根据使用目的不同将该药物做成不同的剂型结构,同时同一剂型结构又可以根据需求制成不同的剂型。结论:口服缓控释制剂剂型结构对体外释药有较大的影响。     

数学模型在顺铂等渗性腹腔化疗中的应用研究

通过6只犬的腹腔化疗,测得腹腔液、股静脉和门静脉的血药[浓度,以及数理模型的推导,给出顺铂在体内药物扩散、药物吸收及吸收速度函数。其结果不仅给临床顺铂腹腔化疗提供理论依据而且提出研究体内药物释放,药物吸收量及药物吸收速率的方法。     

全自动注药泵经深静脉的应用及护理

5-氟尿嘧啶(5-FU)是治疗消化道恶性肿瘤的基本药物。由于5-FU是时间依赖性药物,半衰期仅为15~20分钟,为达到恒定的血药浓度,适合小剂量、长时间静脉持续给药,以增强抗癌疗效。[1]24h的治疗量为0.375g,而一个疗程常需14d~21d的持续静脉输入,如果采用普通输液泵输入,将会给病人带来诸多不便。我科自2008年开始将便携式全自动化疗泵用于5-FU的临床给药,解决了上述问题,取得了理想效果。现将体会总结如下。     

人参总皂苷渗透泵控释片的片芯处方研究

目的:以中药人参的有效部位人参总皂苷为模型药物,进行人参总皂苷渗透泵片的片芯处方研究,以确定其最终片芯处方.方法:采用单因素考察法,从制剂的成型和体外释药特征角度,对人参总皂苷渗透泵片片芯的稀释荆、黏合剂、渗透活性物质和润滑荆进行了筛选.结果:人参总皂苷渗透泵片的最终片心处方为:人参总皂苷提取物100mg,乳糖235mg,淀粉118mg,氯化钠33mg,滑石粉3%～6%.结论:该片心处方辅料来源广泛,利于片心成型,并具有较好的体外释药行为,为人参总皂苷渗透泵控释片的进一步研究打下了基础.     

超声介导镇痛药物透皮吸收研究进展

现阶段,临床中常用的镇痛药物多采用口服或注射给药的方式,具全身不良反应多,患者依从性差等缺点,透皮给药作为一种非侵入性给药方式,相对于这些有很多显著的优势,如使用方便,患者痛苦少等。但是,如何克服皮肤的低渗透性一直是该种给药方式发展的瓶颈。近年来,使用超声能量增强镇痛药物在皮肤上的的渗透性成为新的研究热点,各项研究发现,低频超声对药物的增透效果尤为显著。本文通过检索各国文献,对超声介导镇痛药物透皮吸收的原理,临床前试验和临床试验进行综述。     

肠道病原菌侵袭素在药物纳米载体中的应用

口服给药是药物递送系统中的优选途径。然而,在通过胃肠道时,肠细胞的低渗透性经常会阻碍药物的有效递送。包囊药物能够解决这一问题的关键,取决于其中的细胞侵袭性靶向基团包裹的纳米颗粒系统。这种药物递送系统的侵入特性是由细菌侵袭素的关键成分提供,这些成分具有快速调节药物穿越肠细胞的作用,从而促进宿主细胞对药物的有效吸收。此综述重点阐述细菌侵袭系统,对合适的侵袭素分别从功能和分子结构、作为靶向药物的相对价值以及在使用过程中可能存在的误区依次进行探讨。此外,对口服给药方法的改进和未来前景也进行了讨论。     

海藻酸钠漂浮微囊的制备以及载药应用研究

目的:本文研究了一种海藻酸钠漂浮微囊的制备方法用以实现胃部持续给药。方法:采用微胶囊发生器制备海藻酸钠漂浮微囊,壁材为海藻酸钠,芯材为食用油的漂浮微囊,衡量不同的制备参数对微囊的理化特性影响;采用克拉霉素作为模型脂溶性药物,测量漂浮药物递送系统的控制释放性质、以及微囊载药特性和小鼠体内漂浮验证。结果:成功制备出了具有漂浮特性的海藻酸钠微囊,其中泵送速度对微囊性质的影响最大。制备出的微囊具有低细胞毒性,可以实现90%的药物包埋率。此外,微囊可以在小鼠的胃中保存超过6小时,具有良好的漂浮特性。结论:海藻酸钠漂浮微囊是一种有效的胃部药物递送系统,可明显延长药物在胃部的滞留时间。     

降钙素葡聚糖颗粒缓释微球的研究

目的：降钙素（一个由32个氨基酸组成的多肽）是治疗骨质疏松的首选药之一。降钙索的劣势是其半衰期过短,需要一天一次注射给药,本实验旨在制备突释小,药物释放浓度稳定的降钙素微球制剂。方法：制备降钙素羧酸葡聚糖颗粒和降钙素硫酸葡聚糖颗粒组合物,分别将其包裹于PLGA微球内,制备成降钙素组合微球,采用C18反相色谱柱研究药物的包封率和体外释放行为。结果：所制得的降钙素葡聚糖颗粒缓释微球体外释放一个月,释放曲线比较完美,接近零级释放。结论：本研究制得的降钙素葡聚糖颗粒缓释组合微球能实现理想的体外缓释效果,为后期药动学实验提供基础。     

A simulation study of the anomalous osmotic behavior of red cells

The factors responsible for movements of water across cell membranes were described mathematically and incorporated into a model which simulates water balance in the cell. Included in the model are a variable charge and osmotic coefficient of hemoglobin, a Na/K pump whose rate varies with ionic concentrations, and the standard electroneutrality and osmotic equilibrium assumptions. The model was used to investigate the phenomena whereby human red cells placed in media of varying tonicities exhibit steady state volume changes less than those predicted by van't Hoff's Law. The model results showed that this anomalous osmotic behavior was primarily due to changes in the osmotic coefficient of hemoglobin as its concentration in the cell varied. A second factor accounting for a part of this behavior was the alteration in the rate of the Na/K pump due to intracellular ionic concentration changes as cell volume varied. The effect of variable electrical charge on the hemoglobin molecule was found to be in the wrong direction to account for the observed osmotic behavior. Also, this effect was seen to produce relatively large changes in cell membrane potential, a result inconsistent with experimental data. It was concluded from the model results that the anomalous osmotic behavior of human red cells is primarily due to the variation in the osmotic coefficient of hemoglobin as the cell volume changes, and that the variable charge effect on the hemoglobin molecule, if it exists, does not play a role in this response.     

Potassium reduces lithium toxicity: Circadian rhythm actions are maintained

We tested whether a high potassium diet alters lithium's effects on locomotor activity rhythms to the same extent as it prevents lithium toxicity. Rats fed a standard diet containing 0.47% potassium lost weight after subcutaneous implantation of an osmotic pump delivering 1.35 mg of lithium chloride per hour, and most died or became sick within three weeks after implantation. In contrast, all rats fed a diet containing 4.1% potassium gained weight at the same rate regardless of whether they had received lithium infusions or placebo. In a second experiment, lithium administration by either diet or osmotic pump delayed wheel running rhythms, showing that lithium's central nervous system action did not depend on potassium intake or method of lithium administration. Dietary potassium supplementation may provide a useful strategy for improving the therapeutic index of lithium treatment.     

Subcutaneous Angiotensin II Infusion using Osmotic Pumps Induces Aortic Aneurysms in Mice

Osmotic pumps continuously deliver compounds at a constant rate into small animals. This article introduces a standard protocol used to induce aortic aneurysms via subcutaneous infusion of angiotensin II (AngII) from implanted osmotic pumps. This protocol includes calculation of AngII amount and dissolution, osmotic pump filling, implantation of osmotic pumps subcutaneously, observation after pump implantation, and harvest of aortas to visualize aortic aneurysms in mice. Subcutaneous infusion of AngII through osmotic pumps following this protocol is a reliable and reproducible technique to induce both abdominal and thoracic aortic aneurysms in mice. Infusion durations range from a few days to several months based on the purpose of the study. AngII 1,000 ng/kg/min is sufficient to provide maximal effects on abdominal aortic aneurysmal formation in male hypercholesterolemic mouse models such as apolipoprotein E deficient or low-density lipoprotein receptor deficient mice. Incidence of abdominal aortic aneurysms induced by AngII infusion via osmotic pumps is 5 - 10 times lower in female hypercholesterolemic mice and also lower in both genders of normocholesterolemic mice. In contrast, AngII-induced thoracic aortic aneurysms in mice are not hypercholesterolemia or gender-dependent. Importantly, multiple features of this mouse model recapitulate those of human aortic aneurysms.     

A long-term stable and adjustable osmotic pump for small volume flow based on principles of phloem loading

An adjustable pump for microfluidics employing principles of osmoregulation analogous to those of phloem loading in plant leaves has been constructed and tested. Volume flow arises in a hollow fibre with vapour-permeable hydrophobic membrane. The fibre is connected to a source chamber filled with salt crystals and saturated salt solution. The source chamber takes up water through a relatively small membrane area and delivers saturated salt solution to one end of the capillary flow path within the hollow fibre. A stationary osmotic gradient is sustained in the hollow fibre lumen by constant input of saturated salt solution and radial osmotic water absorption. The strong temperature dependence of isothermal membrane distillation enables adjustment of the flow rate up to 20 nL/s. The pump provides pulse-free flow of any liquid with constant rate for at least 26 days without recharging the source chamber. Backpressures up to 1 bar decrease the flow rate by less than 4%. The volume delivered at a constant rate is more than 40 times larger than the volume of the source chamber. Osmoregulatory pumps of the described type may be useful for microinfusion, microdialysis and analytical microsystems.     

Controlled Porosity Solubility Modulated Osmotic Pump Tablets of Gliclazide

A system that can deliver drug at a controlled rate is very important for the treatment of various chronic diseases such as diabetes, asthma, and heart disease. Poorly water-soluble drug with pH-dependent solubility such as gliclazide (GLZ) offers challenges in the controlled-release formulation because of low dissolution rate and poor bioavailability. Solid dispersion (SD) of GLZ consisted of hydroxypropyl cellulose (HPC-SSL) as a polymeric solubilizer was manufactured by hot melt extrusion (HME) technology. Then, controlled porosity osmotic pump (CPOP) tablet of gliclazide was designed to deliver drug in a controlled manner up to 16 h. The developed formulation was optimized for type and level of pore former and coating weight gain. The optimized formulation was found to exhibit zero order kinetics independent of pH and agitation speed but depends on osmotic pressure of dissolution media indicated that mechanism of drug release was osmotic pressure. The in vivo performance prediction of developed formulation using convolution approach revealed that the developed formulation was superior to the existing marketed extended-release formulation in terms of attaining steady state plasma levels and indicated adequate exposure in translating hypoglycemic response. The prototype solubilization method combined with controlled porosity osmotic pump based technique could provide a unique way to increase dissolution rate and bioavailability of many poorly water-soluble, narrow therapeutic index drugs used in diabetes, cardiovascular diseases, etc.KEY WORDS: convolution approach, gliclazide, hot melt extrusion (HME), hydroxypropyl cellulose, solid dispersion     

Suppressed in vitro blastogenic responsiveness of rat spleen cells after continuous infusion of endotoxin by an implanted osmotic pump

Continuous infusion of a gram-negative bacterial endotoxin in relatively small doses into rats by means of an implanted osmotic pump was studied. The model system was designed to examine the effects of endotoxin on the blastogenic response of spleen cells to the endotoxin itself and to a nonspecific T-cell mitogen, concanavalin A (Con A). Rats were implanted with an osmotic pump which delivered saline for the first 42 hr to provide postsurgical recovery before the onset of endotoxin infusion. Previous studies had shown that during the first 1-4 days after administration of endotoxin marked alterations of metabolism and some changes in physiologic parameters such as blood pressure and in vitro myocardial performance occurred. In the present study the blastogenic responsiveness of spleen cells to endotoxin itself as well as to the nonspecific T-cell mitogen Con A was markedly decreased after several days of continuous administration of endotoxin. Control animals receiving only saline for the same period of time showed a similar depression of blastogenic responsiveness to the lipopolysaccharide (LPS), as well as to Con A, however, with a delay of 2-4 days before comparable levels of suppression became evident. These results indicate that marked alterations of immune competence as measured by blastogenesis of spleen cells to Escherichia coli LPS and to a mitogen such as Con A may occur after implantation of an osmotic pump, with or without continuous infusion of endotoxin. Further studies seem warranted to determine the role of the foreign body reaction to the osmotic pump as well as to the endotoxin administered by the pump.     

Fixation of neural tissue for electron microscopy with an electronically controlled perfusion pump

Many attempts to improve the perfusion of mammalian tissues aim at changes of the osmotic pressure. We describe a method for fixation of nervous tissues controlling both the hydrostatic pressure and the flow rate of a perfusion solution. The constancy of these parameters is guaranteed by an electronically controlled perfusion pump. Thus, a more uniform and complete preservation can be achieved. Further advantages of this method include provision for a rapid succession of rinsing and fixation solution and a continuous control of the hydrostatic pressure during perfusion.     

Splenocyte blastogenesis suppressed in rats implanted with an osmotic pump.

Rats implanted subcutaneously with an empty osmotic pump connected by a polyethylene catheter to a jugular vein for 5 to 10 days evinced a decreased splenocyte responsiveness to blastogenic stimulation in vitro to bacterial lipopolysaccharide, a known B cell stimulator, as well as to the plant mitogens pokeweed mitogen (PWM), a known stimulator of T and B cells, and Concanavilan A, a known T cell stimulator. The surface of the implanted pumps became infiltrated with lymphoid cells, especially macrophages. Suppression of blastogenic responsiveness after implantation for 10 days with an empty pump or even a pump dispensing pyrogen free saline only in a continuous manner was nearly as marked as that which occurred at 2-5 days after continuous infusion with endotoxin. These depressed blastogenic responses, although less, were also evident when rats were implanted with a catheter into a jugular vein connected by means of a swivel to either an empty pump or one dispensing pyrogen free saline. Suppression of blastogenic responsiveness was not related to alteration in serum complement or corticosteroid levels. Since administration of immunomodulatory substances systemically to individuals often involves implantation of an osmotic pump, investigation into the mechanisms of lymphoid cell suppression associated with an implanted pump itself has potential significance.     

Osmoregulation in the Avena Coleoptile : CONTROL OF SOLUTE UPTAKE IN PEELED SECTIONS

Peeled Avena sativa coleoptile sections (i.e. sections from which the epidermis has been removed) have been used to study the control of solute uptake under conditions where the uptake is not limited by the cuticular barrier. In the presence of 2% sucrose, auxin enhances the rate at which the total osmotic solutes increase, but this appears to be a response to the increased growth rate, inasmuch as the auxin effect is eliminated when growth is inhibited osmotically. When sections are incubated in sucrose or in 20 millimolar NaCl, the osmotic concentration increases until a plateau is reached after 8 to 24 hours. Auxin has no effect on the initial rate of increase in osmotic concentration but causes the osmotic concentration to reach a plateau earlier and at a lower osmotic conentration value. This difference in steady-state osmotic concentration is, in part, a response to auxin itself, as it persists when auxin-induced growth is inhibited osmotically. The upper limit for osmotic concentration does not appear to be determined by the turgor pressure, inasmuch as a combination of sucrose and NaCl gave a higher plateau osmotic concentration than did either solute alone. We suggest that the rate of solute uptake is determined by the availability of absorbable solutes and by the surface area exposed to the solutes. Each absorbable solute reaches a maximum internal concentration independent of other absorbable solutes; the steady-state osmotic concentration is simply the sum of these individual internal concentrations.